1,5-dihydro-2h-1,4-benzodiazepine

ABSTRACT

NOVEL BENZODIAZEPIN-2-ONES HAVING AN ETHYLENIC LINKAGE JOINING POSITIONS 3 AND 4. THESE COMPOUNDS ARE INTERMEDIATES IN A PROCESS FOR PREPARING DIHYDRO BENZODIAZEPINES FROM TETRAHYDRO BENZODIAZEPINES. DIHYDRO BENZODIAZEPINES ARE USEFUL AS MUSCLE RELAXANTS, SEDATIVES AND ANTICONVULSANTS.

United States Patent 3,706,734 1,5-DIHYDRO-2H-1,4-BENZODIAZEPINE RodneyIan Fryer, North Caldwell, and Leo Henryk Sternbach, Upper Montclair,N.J., assignors to Hoffmann-La Roche Inc., Nutley, NJ.

No Drawing. Original application Jan. 25, 1968, Ser. No. 700,348, whichis a continuation-in-part of application Ser. No. 614,009, Feb. 6, 1967.Divided and this application Apr. 15, 1971, Ser. No. 133,739

Int. Cl. C07d 53/06 US. Cl. 260-2393 D 9 Claims ABSTRACT OF THEDISCLOSURE Novel benzodiazepin-Z-ones having an ethylenic linkagejoining positions 3 and 4. These compounds are intermediates in aprocess for preparing dihydro benzodiazepines from tetrahydrobenzodiazepines. Dihydro benzodiazepines are useful as muscle relaxants,sedatives and anticonvulsants.

RELATED CASES This application is a division of US. patent applicationSer. No. 700,348, filed Ian. 25, 1968 in the name of Rodney Ian Fryerand Leo Henryk Sternbach, now US. Pat. No. 3,625,957 which is in turn acontinuation-in-part of US. patent application Ser. No. 614,009, filedFeb. 6, 1967, now abandoned. The benefit of the dates of theseearlier-filed applications is hereby claimed.

BRIEF SUMMARY OF THE INVENTION The present invention relates to novelchemical processes and to novel intermediates useful in such chemicalprocedures. More particularly, the present invention relates to novelchemical processes for preparing known compounds useful aspharmacological agents by virtue of their pharmaceutical activity and tonovel intermediates useful in such preparative techniques.

DETAILED DESCRIPTION The present invention in detail relates toprocesses for preparing known compounds which can be characterizedbroadly in a chemical sense as being dihydro-S-aryl-lH-1,4-benzodiazepines and which are of the formula wherein A is selectedfrom the group consisting of phenyl, pyridyl and halophenyl; B isselected from the group consisting of carbonyl and methylene; R and Rare selected from the group consisting of halogen, preferentially,chlorine and bromine, nitro, trifiuoromethyl and hydrogen; R is selectedfrom the group consisting of hydrogen, lower alkyl and lower alkenyl andR is selected from the group consisting of hydrogen and lower alkyl.

By the term halogen as employed herein, all four forms thereof areintended, i.e., chlorine, bromine, fluorine and iodine, unless otherwisespecified. By the term lower alkyl as utilized herein, either alone orin combination with another radical, straight or branched chainhydrocarbon groups containing l-7, most preferably 14, carbon atoms inthe chain are contemplated. Representative of lower alkyl groups aremethyl, ethyl, isopropyl, tertiary butyl and the like. The term aryl" asutilized herein is intended to connote, for example, a phenyl group, asub- Patented Dec. 19, 1972 wherein A, B, R, R R and R are as above witha member selected from the group consisting of an arylsulfonyl halide, alower alkyl sulfonyl halide and a lower alkanoyl group providing agent.Representative of aryl sulfonyl halides suitable for the purposes of thepresent invention are tosyl halide, e.g., para-toluene-sulfonyl chlorideand benzene sulfonyl halide, e.g., benzene-sulfonyl chloride. Suitablelower alkyl sulfonyl halides are illustrated by mesyl halide, e.g.,methane and sulfonyl chlo ride. Suitable lower alkanoyl group providingagents are illustrated by acetic anhydride, acetyl chloride and thelike. Most advantageous for the purposes of this aspect of the presentinvention are aryl sulfonyl halides and lower alkyl sulfonyl halides.Especially preferred is tosyl chloride or mesyl chloride.

By proceeding in the manner described above, there results a compound ofthe formula III wherein A, B, R, R R and R are as above and X isselected from the group consisting of aryl sulfonyl, e.g., benzenesulfonyl, toulene sulfonyl and the like, alkyl sulfonyl, e.g., mesyl andthe like, and lower alkonayl, e.g. acetyl.

This process aspect is conveniently effected in the presence of an inertorganic solvent such as an alkanol, e.g., ethanol and methanol, an ethersuch as diethyl ether and tetrahydrofuran, dimethylformamide, pyridine,a tertiary amine such as tertiary butyl amine or triethyl amine and thelike. Suitably, an acid acceptor is provided to the reaction zone toaccept the hydrohalic acid formed when utilizing a halide, e.g., anarylsulfonyl halide or an alkyl sulfonyl halide, with a compound of theFormula II above. Suitable acid acceptors are tertiary amines, pyridineand the like. In a preferred embodiment, the acid acceptor is providedin excessive amounts whereby it can serve a two-fold purpose, i.e., bothas the solvent medium in which the reaction is effected and as an acidacceptor. In a particular advantageous process variation, the reactionis effected in the presence of pyridine whereby the capability ofpyridine to serve both as an acid acceptor and as a solvent medium isutilized.

Temperature and pressure are not critical aspects of the first stage ofthe process involving the conversion of the compound of the Formula IIabove to the corresponding compound of the Formula IH. However, thereaction is 3 most preferably effected at about room temperature andabove.

Compounds of the Formula III above wherein X is the lower alkanoyl groupformyl, B is methylene, A is a phenyl group or a halophenyl group and Ris lower alkyl, i.e., l-loweralkyl-1,2,3,5-tetrahydro-phenyl-1,4-benzodiazepine 4-carboxaldehydes ofthe formula lower alkyl R l IIIa wherein R and R are selected from thegroup consisting of halogen, preferentially, chlorine and bromine,nitro, triiluoromethyl and hydrogen and R is selected from the groupconsisting of hydrogen and halogen,

can also be prepared by treating a compound of the formula R lower alkylNCHzCI:I\2

R1 IV wherein R and R are as above with a compound of the formula -CHOwherein R is as above in the presence of formic acid whereby to obtainthe corresponding compounds of the Formula III above wherein R and R areas above, X is the lower alkanoyl group formyl, B is methylene and A isphenyl or halophenyl, i.e., compounds of the Formula lIIa above.

Reaction conditions are not critical when reacting a compound of theFormula IV above with a compound of the Formula V above whereby toobtain the corresponding compound of the Formula IIIa above. Thus, thereaction can be effected at room temperature, at atmospheric pressureand/ or above or below room temperature. However, preferentially, thereaction is conducted at elevated temperature, preferably in atemperature range of from about 20 to about 200 C. Suitably, an inertorganic solvent can serve as the reaction medium. Among the many inertorganic solvents suitable for this purpose may be included aromatichydrocarbons such as toluene, xylene, halogenated aromatic hydrocarbons,e.g., chlorobenzene or any other suitable inert organic solvent. In apreferred aspect, however, the formic acid present when performing thereaction of a compound of the Formula IV with a compound of the FormulaV is added in excess whereby it performs the dual function of servingboth as a reaction participant and as the medium in which the reactionis effected. By this simple expedient, there is provided to the reactionzone, a substance necessary to a successful performance of the reaction,as well as the medium in which the reaction is conducted.

Compounds of the Formula IV above are prepared by treating an N-loweralkyl substituted aniline of the formula R lower alkyl Ri VI wherein Rand R are as above with ethyleneimine in the presence of an aproticLewis acid such as, for example, boron triifiuoride, titaniumtetrachloride, aluminum chloride and the like (preferentially, aluminumchloride) and an inert organic solvent, for example, a hydrocarbon suchas benzene, toluene and the like, whereby to prepare a compound of theFormula IV above.

While temperature and pressure are not critical aspects in the formationof a compound of the Formula IV above thusly, elevated temperatures arepreferred, e.g., preferably at about the reflux temperature of thereaction medium. The alternate method for preparing compounds of theFormula IIIa above is not part of the present invention, but such isdisclosed herein in order that the disclosure may be complete.

The second stage of the process of the present invention involves theconversion of a compound of the Formula III above (and of course acompound of the Formula IIIa above included within the genus representedthereby) into a compound of the Formula I above. This reaction iseffected in the presence of a base and an inert organic solvent. Allthat is required of the base is that it be suitable for the purposes ofthe present invention, that is, that it effect the conversion of acompound of the Formula III above and a compound of the Formula IIIaabove to the corresponding compound of the Formula I above. Among themany suitable bases can be included alkali metal lower alkylates such assodium rnethoxide, potassium tertiary butoxide and the like and alkalimetal hydrides, such as sodium hydride. Bases such as aqueous alkalimetal hydroxides e.g., aqueous sodium hydroxide and aqueous potassiumhydroxide and the like can also be efficaciously utilized for thepurposes of the present invention when compounds of the Formula IIIwherein X is benzene sulfonyl or alkyl sulfonyl are to be converted intothe corresponding compounds of the Formula I above. As is noted above,any suitable conveniently available inert organic solvent can beutilized in the conversion of the compounds of the Formula III above tothe corresponding compound" of the Formula I above. Representative, butby no means exclusively so, of inert organic solvents, suitable for thepurposes of the present invention are dimethylformamide,dimethylsulfoxide, tetrahydrofuran and the like. Here again, temperatureand pressure are not critical aspects of this conversion step. However,it has been observed that temperatures of from about 0 to about mostpreferably, from about 25 to about 80 C., are advanta-geous since thehighest yields of the desired endproduct is obtained when the reactionis conducted within this preferred temperature range.

When preparing a compound of the Formula I above wherein B represents acarbonyl group, by treating a corresponding compound of the Formula IIIwherein B is carbonyl with a base, it has been observed that a compoundof the formula VII wherein A, R, R R and R are as above results, as anintermediate. By treating this intermediate with a base, it can beconverted into the corresponding compounds of the Formula I above withor without isolating it from the reaction medium in which it isprepared.

Thus, a compound of the Formula III above wherein B is carbonyl abovecan be treated with a base of the type identified fully above in aninert organic solvent of the character set forth and in the mannerdescribed above and the reaction interrupted when a compound of theFormula VII above is obtained. Said compound of the Formula VII can thenbe further reacted with a base preferentially present in a polar solventsuch as water, a lower alkanol, e.g., ethanol and the like, which may bethe same or different from the last-mentioned base of the type describedabove whereby a compound of the Formula I above wherein B is carbonyl isobtained. On the other hand, a compound of the Formula III above whereinB is carbonyl can be treated with a base until the correspondingcompound of the Formula I above wherein B is a carbonyl is obtainedwithout interrupting the reaction or isolating an intermediate of theFormula VII above. These variations are illustrated in the examples. Theisolation of a compound of the Formula VII above, if desired, is morereadily effected if there is utilized an anhydrous medium as thereaction solvent.

In a preferred embodiment in all of the formulae illustrated above, R ishydrogen and R is joined to the fused portion of the benzodiazepinenucleus at the 7-position thereof (or in the corresponding position ofthe compound illustrated). Furthermore, when A represents a pyridylgroup, the pyridyl group is preferentially joined to the benzodiazepinenucleus at the 2-position thereof. Moreover, when A represents ahalophenyl group, the halogen group is joined to the phenyl ring in the2-position thereof and is preferentially fluorine. In the most preferredembodiment in all of the formulae above, R, R and R are all hydrogen, Ris selected from the group consisting of hydrogen and lower alkyl, mostpreferentially methyl, R is halogen, most preferably, chlorine orbromine and is joined to the fused benzo ring of the benzodiazepinenucleus in the 7-position thereof and A is the unsubstituted phenylgroup.

The foregoing is a description of a main synthetic route to thecompounds of the Formula I above. It will be readily apparent to thoseskilled in the art that variations in these preparative techniques arepossible.

The following examples are illustrative but not limitative of thepresent invention. All temperatures therein are in degrees centigrade.

Example 1 A solution of 14.0 g. (0.051 m.) of 7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in 50 ml. of pyridineat reflux temperature, was treated with a solution of p-toluenesulfonylchloride 11.7 g., 0.0615 111.) in 50 ml. of pyridine (addition timemin.) and was then heated under reflux for 1.5 hr. The hot reactionmixture was poured into 500 ml. of water and a black oil separated. Thewater was decanted and the oil was dissolved in 200 m1. ofdichloromethane. The dichloromethane solution was washed with water (3 X400 ml.), saturated brine solution (1 X 100 ml.), dried over anhydroussodium sulfate, filtered, and evaporated to near dryness. Benzene wasadded and the solution was again evaporated to dryness to give a darkoil. The residual oil was dissolved in a small volume of benzene andfiltered over a pad of florisil, which had been premoistened withhexane. A pale yellow solution was obtained on continued elution withbenzene. The solution was evaporated to dryness to give an oil. Uponcrystallization of the oil from an ether-hexane mixture, 7- chloro2,3,4,5tetrahydro-1-methyl-5-phenyl-4(p-toluenesulfonyl)-lH-l,4-benzodiazepinewas obtained as white crystals, M.P. 110-117". After recrystallizationfrom a di chloromethane-hexane mixture, the product melted at M.P.127-130.

Example 2 A solution of 3.0 g. (0.007 m.) of 7-chloro-2,3,4,5-tetrahydro 1 methyl-5-phenyl-4(p-toluenesulfonyl)-1H 1,4-benzodiazepinein 35 ml. of dry N,N-dimethylformamide was treated with 0.3 g. (0.008m.) of a sodium hydride dispersion in mineral oil. The reaction mixturewas stirred at room temperature for two hours and then allowed to standfor 48 hours. The reaction mixture was poured into 100 ml. of water andextracted with dichloromethane (2X ml.). The dichloromethane extractswere combined, washed with water (3 x 200 ml.), saturated brine solution(1X ml.), dried over anhydrous sodium sulfate, filtered and evaporatedto dryness. The residual yellow oil was dissolved in 30 ml. of absoluteethanol and treated with 1.2 ml. of a 5.56 N solution of hydrogenchloride in ethanol. The ethanol was evapo rated, and the residual oilwas crystallized from a mixture of isopropanol and ether to give7-chloro-2,3-dihydro-1- methyl-S-phenyl-lH-l,4-benzodiazepinehydrochloride as yellow prisms, M.P. 240-250".

Example 3 A solution of 50.0 g. (0.184 m.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl 2H 1,4-benzodiazepin-2-one in 100 ml. of pyridinewas heated to reflux. A warm solution of 42.0 g. (0.22 m.) ofp-toluene-sulfonyl chloride in 100 ml. of pyridine was added to thereaction mixture over a 20 min. period. The reaction mixture was heatedunder reflux for 1.5 hrs. and was then poured into 1 l. of water. Themixture was stirred until a brown solid precipitated. The precipitatewas collected by filtration and washed with four 500 ml. portions ofwater, two 300 ml. portions of ethanol, and 200 ml. of ether. Theprecipitate was then recrystallized from a mixture of chloroform andethanol giving 7chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-to'luenesulfonyl)-2H-1,4-benzodiazepin2 one as white prisms, M.P. 244250. Recrystallization of the productfrom chloroform-ethanol gave the compound as white prisms, M.P. 246252.

Example 4 A solution of 10 g. (0.0234 m.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl-4-(p-toluenesulfonyl) 2H 1,4- benzodiazepin-Z-one in65 ml. of N,N-dimethylformamide was treated with a solution of sodiummethoxide in methanol (0.028 m. of NaOCH at room temperature. Theresulting yellow solution was stirred for 20 min., cooled to 5 and nexttreated with 2.9 ml. of (0.047 m.) of methyl iodide. The resultantmedium was stirred at 510 for 10 min., and then at room temperature for1.5 hr. The reaction mixture was poured into 200 ml. of water andextracted with 200 ml. of dichloromethane. The dichloromethane wasWashed with water (3X 300 ml.), saturated brine solution, dried overanhydrous sodium sulfate and evaporated to dryness. The residual yellowoil which remained after evaporation was crystallized fromdichloromethane-ether to give 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl) 2H 1,4-benzodiazepin-Z-one aswhite needles, M.P. 260-262".

Example 5 A solution of 4.0 g. (0.009 m.) of7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl) 2H1,4- benzodiazepin-Z-one in 35 ml. of N,N-dimethylformamide was treatedwith 0.4 g. (0.01 m.) of a 60% sodium hydride dispersion in mineral oil.The so-obtained reaction mixture was allowed to stand at roomtemperature for 55 hr., poured into 100 ml. of water which was thenextracted with 100 ml. of dichloromethane. The dichloromethane extractwas washed with water (3X 100 ml.), saturated brine solution, dried overanhydrous sodium sulfate and evaporated to dryness. The residual oil wascrystallized from an acetone-hexane mixture to give 7-chloro-1,3-dihydro-l-methyl 5 phenyl-2H-1,4-benzodiazepin-Z-one as whiteprisms melting at 127-130.

Example 6 A solution of 19.5 g. (0.0456 m.) of 7-chloro-1,3,4,5-tetrahydro phenyl-4-(p-toluenesulfonyl) 2H 1,4- benzodiazepin-Z-one in150 ml. of dry benzene was treated with 4.0 g. (0.10 m.) of a 60 percentsodium hydride dispersion in mineral oil. The reaction mixture washeated under reflux for 20 hr., and was then poured into 300 ml. ofwater. Hydrochloric acid was added until approximately pH 7. The layerswere separated and the aqueous phase was extracted with dichloromethane(2X 11.). The organic layers were combined, washed with water (3X 500ml.), saturated brine solution (1 100 ml.), dried over anhydrous sodiumsulfate, filtered and evaporated to dryness. The residual oil wascrystallized from a mixture of dichloromethane-hexane to .give 7-chloro-1,5-dihydro-5-phenyl 2H 1,4-benzodiazepin-2- one as white prisms,M.P. 202-210".

Example 7 A solution of 0.5 g. (0.002 m.) of7-chloro-1,5-dihydro-5-phenyl 2H 1,4-benzodiazepin-2-one in 15 ml. ofN,N-dimethylformamide was treated with a solution of sodium methoxide inmethanol (0.011 m. of NaOCH The mixture was allowed to stand at roomtemperature for 0.5 hr. and then poured into 50 ml. of water.Hydrochloric acid was added until the pH reached approximately 7 and themixture was extracted with dichloromethane (2x 40 ml.). The combineddichloromethane extracts were washed with water (3X 60 ml.), saturatedbrine solution (1X 30 ml.), dried over anhydrous sodium sulfate,filtered, and evaporated to dryness. The residual oil was crystallizedfrom a mixture of dichloromethane and hexane to give 7-chloro 1,3dihydro 5 phenyl-2H-1,4- benzodiazepin-Z-one as white prisms, M.P.215-221.

Example 8 A solution of 5.0 g. (0.0117 In.) of 7-ch'loro-1,3,4,5-tetrahydro-S-phenyl 4 (p toluenesulfony1)-2H-1,4- benzodiazepin-Z-one in35 ml. of N,N-dimethylformamide was treated with 1.0 g. (0.026 m.) of a60% sodium hydride dispersion in mineral oil. The tan solution wasstirred at room temperature for 1 hr. and then allowed to stand for 48hrs. The reaction mixture was poured into 200 ml. of water and extractedwith 100 ml. of dichloromethane. The dichloromethane extract was washedwith water (3X 500 ml.) saturated brine solution (1X 100 ml.), driedover anhydrous sodium sulfate and evaporated to dryness to give an oil.The oil was dissolved in dichloromethane which was concentrated andcooled. The so-obtained concentrate was filtered and was recrystallizedfrom acetone to give 7-chloro-1,3-dihydro 5 phenyl-2H-1,4-benzodiazepin-2-one as white prisms, M.P. 212-214".

Example 9 A solution of 3.0 g. (0.007 m.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl 4 (p-toluenesulfonyl)-2H-1,4- benzodiazepin-Z-one in35 ml. of N,N-dimethy1formamide was cooled to 5 C., and treated with asolution of sodium methoxide in methanol (0.0154 In. of NaOCH Thereaction mixture was allowed to stand for 79 hrs. The reaction mixturewas poured into 200 ml. of water, hydrochloric acid was added until pH 7and the solution was then extracted with 100 ml. of dichloromethane. Theorganic layer was separated and washed with water (3 x 300 ml.),saturated brine solution (1X 100 ml.), dried over anhydrous sodiumsulfate, filtered and evaporated to dryness. The residual oil wascrystallized from a mixture of dichloromethane and hexane to give7-chloro-1,3-dihydro-S-phenyl 2H 1,4 benzodiazepin-Z-one as whiteprisms, M.P. 213-217".

Example 10 A solution of 3.0 g. (0.007 m.) of 7-chloro-1,3,4,5-

tetrahydro 5 phenyl 4 (p-toluenesulfonyl)-2H-1,4- benzodiazepin-Z-one in35 ml. of N,N-dimethylformamide was cooled to 5 C. and treated with 1.7g. (0.0154 In.) of potassium tertiary butoxide. (The solution turneddeep yellow.) The reaction mixture was stirred at 5 C. for one-half hourand then allowed to warm to room temperature and stand for 79 hrs. Thereaction mixture was poured into 200 ml. of water, hydrochloric acid wasadded to pH 7 (approximately) and the solution was then extracted withml. of dichloromethane. The dichloromethane layer was separated andwashed with water (4X 300 ml.), saturated brine solution (1X 100 ml.),dried over anhydrous sodium sulfate, filtered and evaporated to dryness.The residual oil was crystallized from a mixture of dichloromethane andhexane to give 7-chloro-1,3- dihydro-5-phenyl-2H-1,4-benzodiazepin-2-oneas white prisms, M.P. 212-216".

Example 11 A solution of 2.0 g. (0.0047 111.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl 4 (p-toluenesulfonyl)-2H-1,4- benzodiazepin-Z-one in30 ml. of N,N-dimethylformamide was treated with 0.5 ml. of 0.1 N sodiumhydroxide solution. The mixture was stirred at room temperature for 4hrs. and then allowed to stand for 55 hrs. The reaction mixture waspoured into 100 ml. of water, hydrochloric acid was added to pH 7 andthe solution was then extracted with dichloromethane (3 X 50 ml.). Thecombined dichloromethane extracts were washed with water (3X 200 ml.),saturated brine solution (1x 100 ml.), dried over anhydrous sodiumsulfate, filtered and evaporated to dryness. The residual oil wascrystallized from a mixture of dichloromethane and hexane. The productwas then recrystallized two times from acetone to give 7-chloro1,3-dihydro 5 phenyl 2H 1,4 benzodiazepin-Z-one as white prisms, M.P.211-214.

Example 12 A solution of 5.0 g. (0.117 m.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl 4 (p-toluenesulfonyl)-2H-1,4- benzodiazepin-Z-one in40 ml. of tetrahydrofuran was treated with 1.0 g. (0.0258 m.) of a 60%dispersion of sodium hydride in mineral oil and the reaction mixture wasstirred first at room temperature, and then at 60 for 5 hrs. Thereaction mixture was poured into 200 ml. of water, and extracted into100 ml. of dichloromethane. The dichloromethane extract was washed withWater (3 X 300 ml.), saturated brine solution (1X 100.ml.), dried overanhydrous sodium sulfate, filtered and evaporated to dryness. Theresidual oil was crystallized from dichloromethane to give7-cl1loro-1,3-dihydro-5-phenyl-2H-1,4- benzodiazepin-Z-one as whiteprisms, M.P. 210-214".

Example 13 A solution of 5.0 g. (0.0117 in.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl 4 (p-toluenesulfonyl)-2H-1,4-

benzodiazepin-Z-one in 40 ml. of dimethylsulfoxide was treated with 1.0g. (0.0258 In.) of a 60% dispersion of sodium hydride in mineral oil.The reaction mixture was stirred at room temperature for an hour and wasthen allowed to stand for 40 hrs. (The solution turned amber.)

The reaction mixture was poured into ml. of water and extracted with 100ml. of dichloromethane. The dichloromethane extract was .Washed withwater (3X 300 ml.), saturated brine solution (1X 100 ml.), dried overanhydrous sodium sulfate, filtered and evaporated to dryness. Theresidual oil was crystallized from a mixture of dichloromethane andhexane to give 7-chloro-1,3-dihydro- 5 phenyl 2H 1,4 benzodiazepin-Z-oneas white prisms, M.P. 210-214".

Example 14 A suspension of 50 g. (0.183 m.) of 7-chloro-1,3,4,5-tetrahydro 5 phenyl 2H 1,4-benzodiazepin-2-one in 380 ml. of pyridinewas cooled to 5 and treated with 15.6 ml. (0.201 m.) of methanesulfonylchloride (15 min.). The clear yellow solution was warmed to 28 and wasthen stirred at room temperature for 2.5 hrs. The reaction mixture waspoured into a 1.3 l. of water and stirred vigorously. The crystallineprecipitate was collected by filtration and was washed with four 300ml.- portions of water followed by two 200 ml.-portions of ether.Recrystallization of the product from a mixture of chloroform andethanol gave 7-chioro-1,3,4,5-tetrahydro 4 methanesulfonylphenyl-ZH-1,4-benzodiazepin-2-one as white prisms, M.P. 203206.

Example A solution of 3.0 g. (0.0086 in.) of 7-chloro-1,3,4,5-tetrahydro 4 methanesulfonyl 5 phenyl-2H-1,4-benzodiazepin-Z-one in ml.of N,N-dimcthylformamide was treated with 0.76 g. (0.019 m.) of a 60%sodium hydride dispersion in mineral oil. The reaction mixture wasstirred at room temperature for 2 hrs. and then at for 4 hrs.

After cooling to room temperature, the reaction mixture was poured into200 ml. of water, hydrochloric acid was added until pH 7 (approximately)and the resulting mixture was extracted with dichloromethane (2 X 75ml.). The combined dichloromethane extracts were washed with water (3X300 ml.), saturated brine solution (1X 100 ml.), dried over anhydroussodium sulfate, filtered and evaporated to dryness. The residual oil wascrystallized from a mixture of dichloromethane and hexane. The motherliquors were then evaporated to dryness and crystallized from a mixtureof dichloromethane and hexane to give7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-Z-one as whiteprisms, M.P. 210-214.

Example 16 A solution of 10.0 g. (0.034 m.) of 7-chloro-l,3,4,5-tetrahydro 5 (2 fluorophenyl) 2H 1,4-benzodiazepin-2-one in 100 ml. ofpyridine was treated with a solution of 9.5 (0.051 m.) ofp-toluenesulfonyl chloride in ml. of pyridine. The reaction mixture washeated under reflux for two hrs. and poured into 750 ml. of water. Afterstirring for 0.5 hr. the oily precipitate crystallized. The crystalswere collected by filtration, dissolved in a large volume ofdichloromethane, which was dried over anhydrous sodium sulfate, filteredand then concentrated on a steam bath to a small volume. The solutionwas cooled and 7 chloro-l,3,4,5-tetrahydro-5-(2-fiuorophenyl) 4 (ptoluenesulfonyl) 2H-1,4-benzodiazepin-2- one was obtained by filtration.After recrystallization from a mixture of dichloromethane-petrol (B.P.30-60), the product crystallized as white prisms, M.P. 242443".

Example 17 A solution of 3.0 g. (0.0068 m.) of 7-chloro-1.3,4,5-tetrahydro 5 (2 fiuorophenyl) 4 (p-toluenesulfonyl) 2H 1,4benzodiazepin-Z-one in 35 ml. of N,N- dimethylformamide was treated with0.6 g. (0.015 m.) of a sodium hydride dispersion in mineral oil and wasstirred at room temperature for 19 hrs. The reaction mixture was pouredinto 200 ml. of water and hydrochloric acid was added to approximatelypH 7. The reaction mixture was then extracted with dichloromethane (2X75 ml.). The combined dichloromethane extracts were washed with water(4X 600 ml.), saturated brine solution (1x 100 1111.), dried overanhydrous sodium sulfate, filtered and evaporated to dryness. Theresidual yellow oil was crystallized from a mixture of dichloromethaneand hexane. The mother liquors were evaporated to dryness andcrystallized from a mixture of benzene and hexane to give 7-chloro 1,3dihydro 5 (2-fluorophenyl) 2H 1,4 benzodiazepin-Z-one as white prisms,M.P. l96-202.

Example 18 To a solution of 7 chloro 1,2,3,5 tetrahydro 1- methyl 5phenyl-4H-1,4-benzodiazepine 4 carboxaldehyde (1 gm., 3.3 mm.) in dryN,N-dimethylformamide (25 ml.) was added sodium hydride (300 mg. 7.5 mm.of 60 percent w./w. suspension in mineral oil). The mixture was stirredunder dry nitrogen for hrs., and was then poured onto ice. After the icehad melted, the resulting precipitate was recovered, and slurried with 1N acetic acid solution. The mixture was filtered, and the filtrates weremade basic with dilute sodium hydroxide solution, to give crude 7-chloro2,3 dihydro-l-methyl- S-phenyl-lH-1,4-benzodiazepine as an oil, whichwas recovered by extraction with ether. Further purification waseffected by filtration of a benzene solution of the extract through abed of Woelm activity III neutral alumina (10 gm.). Evaporation of thefiltrates afforded the product as a gum. Treatment of the gum withmethanolic hydrogen chloride and ether yielded 7- chloro 2,3 dihydro 1methyl 5 phenyl-lH-1,4- benzodiazepine hydrochloride. Recrystallizationof the hydrochloride from methanol-ether gave orange crystals, M.P.256-257 C. (sealed tube) base '(V).

The preparation of 7-chloro 1,2,3,5 tetrahydro-1- methyl 5phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde is not part of the presentinvention, but such preparation is disclosed herein in order that thedisclosure be complete. Furthermore, the preparation ofN-(pchlorophenyl)-N-methyl-ethylenediamine is not part of the presentinvention but is disclosed herein in order that the disclosure becomplete.

Formic acid (100 ml., 98 percent w./w.) was carefully added toN-(p-chlorophenyl) N methyl ethylenediamine (70 gm., 0.4 mol.), withstirring and while cooling in an ice bath. The so-formed reactionmixture was allowed to warm to 25 C., and was then treated withbenzaldehyde (40 gm., 0.375 mol.). The resultant mixture was then heatedat for 17 hours. After cooling, the mixture was added slowly to astirred mixture of ice, 3 N sodium hydroxide solution, and ether. Thealkaline aqueous layer was separated, further extracted with ether (3X100 ml.) and discarded. The combined ether extracts were washed withwater, dried (MgSO and evaporated, to give an oil. The oil was dissolvedin a mixture of N-hydrochloric acid (500 ml.) and ether (250 ml.). Theether layer was separated, and the aqueous acid layer was furtherextracted with ether (2X 250 ml.). The combined ether extracts werewashed with saturated sodium bicarbonate solution, dried (MgSO andevaporated. Crystallization of the residue from isopropanol gave7-chloro 1,2,3,5 tetrahydro-l-methyl- S-phenyl 4H 1,4 benzodiazepine 4carboxaldehyde as two crops of crystals, M.P. 114-115 and M.P. 121.Recrystallization of the combined crops from hexane attordedcream-colored prisms, M.P. 121-122".

A mixture of 63.8 g. (0.5 m.) of p-chloroaniline and 114 g. (0.6 m.) ofp-toluenesulfonyl chloride in 400 ml. of pyridine was stirred at roomtemperature overnight. Most of the pyridine was then removed in vacuo.The residue was poured into 2 l. of ice-Water and the tosylate extractedwith ether. The ether was extracted with 1 N sodium hydroxide, aqueoushydrochloric acid, water, dried over magnesium sulfate and concentrated.The resulting oil was crystallized from ether, yielding tosyamido-4-chlorobenzene, M.P. 119.5-120.5.

A mixture of 70.4 g. (0.25 m.) of tosylamido4-chloro-- benzene, 700 ml.toluene and 0.3 mole of sodium methoxide in 200 ml. of methanol wasstirred and refluxed for 1 hour. After distilling off most of themethanol. 47.3 ml. (0.5 m.) of dimethyl sulfate was added. The stirringand refluxing was then continued for 5 additional hours. Theprecipitated sodium salt disappeared slowly. Excess dimethyl sulfate wasdestroyed by refluxing an additional 1 /2 hours with 400 m1. of 3 Nsodium hydroxide. The phases were separated and the toluene distilledoff leaving a white crystalline residue. Recrystalliza- 1 1 tion fromethanol gave N-methyl-tosylamido-4-chlorobenzene, M.P. 9293.

61.5 g. (0.208 m.) of N-methyl-tosylamido 4 chlorobenzene were added to580 ml. of sulfuric acid (spec. gravity 1.74) at 105. The mixture wasstirred, heated up to 145 and kept at that temperature for 1 hour. Aftercooling, the solution was made strongly alkaline with 50 percent sodiumhydroxide and the organic base extracted with ether. The organic extractwas dried over potassium hydroxide pellets, concentrated and the residuedistilled in vacuo to yield p-chloro-N-methylaniline, B.P. 74.75 at 0.7mm. Hg.

To 13.3 g. of aluminum chloride and 20 ml. of dry benzene, in a 50 ml.three neck flask equipped with reflux condenser, dropping funnel andstirrer, there was added 14.1 g. (0.1 m.) of gp chloro-N-methylaniline,carefully and with cooling. After complete addition, the mixture washeated until reflux commenced and kept at that temperature for a shortperiod. Freshly distilled ethyleneimine (4.3 g., 0.1 m.) was then slowlydistilled into the reaction vessel from a small flask attached to theformer with a gas-inlet tube by heating the flask. After the additionwas complete, the reaction mixture was stirred for another thirtyminutes and then poured on 200 g. of ice contained in a one liter flaskfitted with a condenser. Solid potassium hydroxide, 50 g., was added tothe resulting solid in small portions, and the material was observed togo into solution. It was then cooled and extracted three times withbenzene. The combined benzene extracts were dried over potassiumhydroxide pellets and concentrated. The residue was distilled in vacuothrough a ten-cm. Vigreux column yielding N-(p-chlorophenyl)-N-methyl-ethylenediamine, B.P. 126-l27 at 0.05 mm. Hg.

Example 19 To a solution of 69 g. (0.25 mole) of crude 7-chloro- 2,3,4,5tetrahydro 1 methyl phenyl-lH-1,4- benzodiazepine in 200 ml. of pyridinewas added 125 ml. of acetic anhydride. The reaction mixture was left atroom temperature for minutes then heated on the steam bath for 35minutes and concentrated in vacuo to dryness. The residue was dissolvedin a mixture of ether and ice cold dilute hydrochloric acid. The etherlayer was separated, washed with water and dilute ice cold sodiumhydroxide, then dried and concentrate in vacuo to dryness. The residuewas crystallized from a mixture of ether and petroleum ether and gave4-acetyl-7-chloro- 2,3,4,5 tetrahydro-l-methyl 5phenyl-lH-1,4-benzodiazepine melting at 106-108.

Example 20 A solution of 1 g. (0.00318 m.) of 4-acetyl-7-chloro- 2,3,4,5tetrahydro 1 methyl 5 phenyl 1H 1,4- benzodiazepine in ml. of dryN,N-dimethylformamide under nitrogen was treated with 0.14 g. (0.00349m.) of 56.9 percent sodium hydride in mineral oil. The mixture was letstand for 60 hrs. It was then stirred at 4045 for 5 hrs. and solventswere removed under reduced pressure. The residue was dissolved in 50 ml.of ether and extracted with 1 N hydrochloric acid (2X 40 ml.). The acidlayers were combined, made basic with ammonium hydroxide and extractedwith 100 ml. of dichloromethane. The organic layer was washed with 50ml. of a saturated brine solution, dried over anhydrous sodium sulfateand evaporated to dryness.

The resulting oil was dissolved in dichloromethane, filtered through 75g. of silica gel, which was then eluted with 400 ml. of dichloromethaneand 500 ml. of ethyl acetate. An excess of ethanolic hydrogen chloridewas added to the ethyl acetate fraction, which was then evaporated todryness. The product was recrystallized twice from isopropanol/ether togive 7-chloro-2,3-dihydro-1- methyl-S-phenyl-IH-1,4-benzodiazepinehydrochloride as orange prisms M.P. 250-254 (sealed tube).

We claim:

1. A compound of the formula wherein A is selected from the groupconsisting of phenyl, pyridyl and halophenyl; R and R are selected fromthe group consisting of hydrogen, halogen, nitro and trifluoromethyl; Ris selected from the group consisting of hydrogen, lower alkyl and loweralkenyl and R is selected from the group consisting of hydrogen andlower alkyl.

2. A compound as in claim 1 wherein A is phenyl or 2-halophenyl, R and Rare both hydrogen, R is halogen or nitro and is joined to the 7-positionof the benzodiazepine nucleus and R is hydrogen or lower alkyl.

3. A compound as defined in claim 1 of the formula7-halo-l,5-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.

4. A compound as defined in claim 2 of the formula 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.

5. A compound as defined in claim 1 of the formula 7 halo 1,5 dihydro 5(2 halo phenyl) 2H- 1,4-benzodiazepin-2-one.

6. A compound as defined in claim 5 of the formula 7 chloro 1,5 dihydro5 (2 halo phenyl) 2H- 1,4-benzodiazepin-2-one.

7. A compound as defined in claim 1 of the formula 7 halo 1,5 dihydro 5(2X phenyl) 1 lower alkyl 2H 1,4 benzodiazepin 2 one wherein X ishydrogen or halogen.

8. A compound as in claim 7 wherein the l-lower alkyl group is methyl.

9. A process for preparing a compound as defined in claim 1 whichcomprises reacting a compound of the formula wherein A is selected fromthe group consisting of phenyl, pyridyl and halophenyl; R and R areselected from the group consisting of halogen, nitro, trifiuoromethyland hydrogen; R is selected from the group consisting of hydrogen, loweralkyl and lower alkenyl; R is selected from the group consisting ofhydrogen and lower alkyl and X is selected from the group consisting ofaryl sulfonyl, alkylsulfonyl and lower alkanoyl with a base in thepresence of an anhydrous solvent medium.

References Cited UNITED STATES PATENTS 3,446,800 5/1969 McCaully260-2393 D HENRY R. JILES, Primary Examiner R. T. BOND, AssistantExaminer US. Cl. X.R. 260-2393 D, 999

mg? 4 UNiTED STATES PATENT QFFEQE CERTIFICATE 0 seem-ewe Patent No.5,706,73 Dated December 19, 1972 lnventoz-(s) Rodney Ian Fryer and LeoHenryk Ste rnbach It is certifi-e' that error agSp-eare in theab'oee-ifiencified-patent and that said Letters Patent are herebycorrectefi as shown below:

Column 12, claim 9, line 44, i

R1 Li R2 0 R- l H I CH-IY R1 A X Signed and sealed this 29th day of May1973.,

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

